LPS-induced liver injury in D-galactosamine-sensitized mice requires secreted TNF-α and the TNF-p55 receptor

Monika Nowak, Gregory C. Gaines, Jason Rosenberg, Rebecca Minter, F. R. Bahjat, John Rectenwald, Sally L.D. Mackay, Carl K. Edwards, Lyle L. Moldawer

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150 Scopus citations

Abstract

Lipopolysaccharide and D-galactosamine induced lethality and apoptotic liver injury is dependent on endogenously produced tumor necrosis factor (TNF)-α. The present study was undertaken to determine whether membrane- associated or secreted TNF-α signaling through the p55 or p75 receptor was responsible for survival and hepatic injury after lipopolysaccharide administration in D-galactosamine-sensitized mice. Transgenic mice expressing null forms of TNF-α, the p55 and p75 receptor, and mice expressing only a cell-associated form of TNF-α were challenged with 8 mg D-galactosamine and 100 ng lipopolysaccharide. Mortality and apoptotic liver injury were only seen in wild-type and p75 knockout mice. p75 Knockout mice had significantly higher concentrations of plasma TNF-α than any other experimental group (P ≤ 0.05) and tended to have the highest mortality and liver injury. In contrast, p55 and TNF-α knockout mice and animals expressing only a cell- associated form of TNF-α exhibited no mortality or liver injury. We conclude that survival and apoptotic liver injury in response to lipopolysaccharide and D-galactosamine are dependent exclusively on secreted TNF-α signaling through the p55 receptor.

Original languageEnglish (US)
Pages (from-to)R1202-R1209
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume278
Issue number5 47-5
StatePublished - Jun 27 2000

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Keywords

  • Apoptosis
  • Hepatitis
  • Septic shock

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Nowak, M., Gaines, G. C., Rosenberg, J., Minter, R., Bahjat, F. R., Rectenwald, J., Mackay, S. L. D., Edwards, C. K., & Moldawer, L. L. (2000). LPS-induced liver injury in D-galactosamine-sensitized mice requires secreted TNF-α and the TNF-p55 receptor. American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 278(5 47-5), R1202-R1209.